Diazinon was produced for the first time by Glysin and Margot by reacting 2-isopropyl-4-methyl-6-hydroxy-pyrimidine (hereafter hydroxypyrimidine) with diethylthiophosphoryl chloride (hereinafter TPC) in an inert solvent, in the presence of potassium carbonate as described in United Kingdom patent number 713,278.
In this heterogeneous reaction the potassium pyrimidin-olate is initially formed by heating the hydroxy-pyrimidine with potassium carbonate in benzene, with simultaneous removal of the water formed. The potassium salt so produced is then reacted with TPC by heating for several hours, the potassium chloride formed extracted by washing with water, and the solvent removed under reduced pressure.
The standard process for the industrial manufacture of diazinon is carried out essentially by means of a 4-stage synthesis, as follows: ##STR1## where R is isopropyl.
Since 1952 numerous patents have issued which have attempted to improve upon the above four-step process. Thus, U.S. Pat. No. 4,111,976 describes an improved optimized formation of the product of the first step.
U.S. Pat. No. 4,014,879 describes an optimum continuous ring closure reaction between the amidine and methyl acetoacetate of the third step.
U.S. Pat. Nos. 4,018,771; 4,052,396 and 4,052,397 describe processes of preparing the hydroxy pyrimidine starting with diketene, where the process of the first two patents respectively are run in the presence of a Lewis acid.
United Kingdom patent 2,083,814 describes a process for preparing the hydroxypyrimidine by reacting the iminoether of the first step with ammonia in methanol as solvent and then reacting the resulting amidine of the second step with excess alkyl acetoacetate in methanol under strongly alkaline conditions.
U.S. Pat. No. 3,205,231 describes a process of preparing 2-fluoromethyl derivatives of the hydroxy-pyrimidine by reacting the 2-fluoromethyl hydroxypyrimidine with an organophosphorous ester halide in the presence of dry, sifted potassium carbonate and lower aliphatic ketones or nitrites as solvent.
U.S. Pat. No. 3,792,132 describes a process for preparing alkyl phenyl phosphates and phosphorothionates, where the phenolic compound is reacted with the organophosphorous compound in the presence of a catalyst system comprising a tertiary amine and an alkali or alkaline earth metal in a ketone or carboxylic acid esters as solvent.
Since 1952 several processes have been described in the literature, which modify the fourth (last) step. Thus, U.S. Pat. No. 4,066,642 describes simultaneously reacting TPC and the hydroxypyrimidine in the presence of an acid acceptor such as sodium or potassium hydroxide while refluxing the inert solvent to remove the water as it is formed without the use of any catalyst.
Various other processes involving the use of a variety of catalysts to shorten the reaction times have been described. Suitable catalysts disclosed are mercury salts (U.S. Pat. No. 3,107,245), copper chloride (U.S. Pat. No. 3,107,246), copper nitrate (U. S. Pat. NO. 3,367,935) and basic copper oxide (Japanese patent specification 75 5249 58).
U.S. Pat. No. 4,326,059 describes a process for preparing diazinon, where the hydroxypyrimidine is reacted with aqueous sodium hydroxide in an aromatic hydrocarbon such as xylene, in the presence of a phase transfer catalyst, by first distilling off the water and then adding the TPC. However, this process requires a reaction time of 4 to 6 hours and still yields strongly colored material.
In the processes which involve the use of catalysts it was found that significant amounts of highly toxic by-products such as thiotepp (mono- or di-thiono-tetraethyl pyrophosphate) are formed. The presence of even small amounts of these by-products in diazinon is undesirable from the point of view of operators or warm blooded animals that may come into contact therewith. Thus, U.S. Pat. No. 3,432,503 discloses a method of removing these by-products by refluxing the diazinon in an inert solvent in the presence of a base such as sodium hydroxide. However, this process not only requires a separate step subsequent to manufacture, but also involves considerable loss of product during work-up.
Recently U.S. Pat. No. 4,323,678 reported a one-pot reaction wherein isobutyryl-aminocrotonic acid amide is cyclized in the presence of an alcohol, the resulting sodium pyrimidinolate precipitated by addition of a non-polar solvent, the alcohol/water removed by fractionation and the sodium pyrimidinolate reacted with TPC at a temperature of 100.degree. C. to 130.degree. C.
More recently, U.S. Pat. No. 5,034,529 reported a process involving mixing MIBK with the hydroxypyrimidine and sodium hydroxide solution, heating the mixture to reflux and azeotropically distilling off water and then adding TPC. While this process works in a reasonable fashion on a laboratory scale, the azeotropic distillation has been found to take too much time (14-20 hours) when carried out industrially.
All of the above methods suffer from a variety of drawbacks. Examples are long reaction times, the need to use catalysts, the need for tricky manipulation of solvents, and/or the need for a separate step to remove toxic by-products. And none of these processes affords high yields of very pure, very slightly colored diazinon.